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Division of Rheumatology
Department of Medicine
University of Alabama at Birmingham
Maria Danila, MD, MSc, MSPH, has disclosed that she has received funds for research support from Amgen, Genentech, Horizon, and Pfizer; has received consulting fees from AbbVie and Amgen; and has ownership interests in Pfizer.
Rheumatoid arthritis (RA) and treatments such as Janus kinase inhibitors (JAKi) have been associated with an increased risk of shingles and concerns about thromboembolic and cardiovascular events. At the 2020 virtual ACR/ARP Convergence, several studies addressed these safety issues. In this commentary, I briefly review key findings for your practice.
Herpes Zoster Vaccine
The recombinant herpes zoster vaccine is the only vaccination available to prevent shingles in the United States, yet there is a paucity of data on its ability to elicit serologic responses in patients with RA. At ACR/ARP 2020, a study from Sweden compared the immunogenicity of standard-dose herpes zoster vaccine in 40 adults with RA receiving JAKi vs 20 healthy adults.
Positive humoral responses were observed in 75% of patients with RA and 100% of controls, and no patient experienced worsening or flare of RA post vaccination.
Although this study had a small sample size, these findings are encouraging for patients and clinicians—they suggest that herpes zoster vaccination is efficacious in this RA subpopulation at high risk for herpes zoster.
Venous Thromboembolism (VTE)
A potential signal for VTE events has been described with all JAKi approved for the treatment of RA in the United States.
At ACR/ARP 2020, results were presented from a recent analysis of VTE incidence among patients with RA receiving upadacitinib, methotrexate, or adalimumab as part of the SELECT upadacitinib phase III clinical trial program.
This study showed that higher body mass index and prior VTE were risk factors for incident VTE in the upadacitinib clinical trials. This was not surprising as these are established risk factors for VTE in the general population.
The investigators concluded that VTE event rates were balanced across upadacitinib doses and active comparator groups in this pooled analysis.
Of importance, no definite conclusion can be drawn about the association of upadacitinib and VTE given the small sample size (especially since VTE was so rare) and the short duration of follow-up (ie, 3 years in the upadacitinib 15-mg group). Further postmarketing studies will be important to clarify the relationship between upadacitinib and VTE.
VTE/Major Adverse Cardiovascular Event (MACE)
Although concerns for VTE have been raised with the use of JAKi, MACE have also been examined. Using data from the clinical trial program for filgotinib—a new selective JAKi under investigation for the treatment of RA—the incidence of MACE and VTE was presented in a pooled analysis at ACR/ARP 2020.
The small sample size notwithstanding (1675 patients receiving filgotinib 200 mg and 1322 receiving 100 mg), the incidence rate of MACE and VTE among people with RA exposed to filgotinib appeared to be low.
Although this is thus far reassuring for filgotinib, it is important for clinicians to remember that the safety of medications, and particularly rare adverse events, is only adequately clarified over longer periods of time than those afforded by clinical trials meant to evaluate efficacy.
Hydroxychloroquine, an important treatment for autoimmune diseases including RA, has been associated with cardiac toxicity when used in combination with other medications for COVID-19. However, at ACR/ARP 2020, a cohort study that included 1328 patients with RA for a total of 8336 patient-years of follow-up found that cardiac dysrhythmias were 39% less likely to occur in patients receiving vs not receiving hydroxychloroquine.
Moreover, there were no significant differences in the risk of myocardial infarction, cardiomyopathy, or conduction disorders among patients receiving vs not receiving hydroxychloroquine. These results are reassuring for patients with RA who depend on hydroxychloroquine to control their disease.
In summary, new data from ACR/ARP 2020 have demonstrated that clinicians managing patients with RA can feel confident in our use of effective therapies such as hydroxychloroquine.
We can also assure our patients of the effectiveness of herpes zoster vaccination.
Finally, although early data are reassuring regarding the cardiovascular safety of the JAKi upadacitinib and filgotinib, I believe we should look for longer-term safety data from postmarketing trials.
How will new safety data on RA therapies influence your practice? Answer the polling question and join the conversation by posting a comment in the discussion section. And for more details on these and other studies from ACR/APR 2020, download Capsule Summaries of all the key data.